Duration of Methotrexate Therapy for Rheumatoid Arthritis
Methotrexate should be continued indefinitely as long-term maintenance therapy for rheumatoid arthritis, as it demonstrates sustained efficacy and acceptable safety over many years, with over 50% of patients continuing treatment at 12 years in community practice. 1, 2
Evidence for Long-Term Use
Based on its acceptable safety profile, methotrexate is appropriate for long-term use without a predetermined stopping point. 1 The evidence supporting indefinite continuation is robust:
In a 12-year follow-up study of 460 RA patients in community practice, 53% were still taking methotrexate at 12 years (irrespective of temporary discontinuations), and 38% if discontinuation for >3 months was counted as treatment failure. 2
RA patients on methotrexate had lower mortality rates compared to those without methotrexate (23/1000 versus 26.7/1000 patient-years) and reduced cardiovascular mortality (HR 0.3; 95% CI 0.2 to 0.7) in a large 6-year prospective study. 1
In meta-analyses and cohorts with 5-12 years follow-up, methotrexate was discontinued less often due to toxicity than other DMARDs, except hydroxychloroquine. 1
When Arthritis Worsens After Stopping
When methotrexate is discontinued, arthritis usually worsens within 3 to 6 weeks, reinforcing the need for continued therapy to maintain disease control. 3
Limited data from long-term studies in adults indicate that initial clinical improvement is maintained for at least two years with continued therapy. 3
Monitoring Requirements During Long-Term Use
Safety monitoring should continue throughout the entire course of therapy, as the risk of adverse effects persists over time. 2
ALT/AST, creatinine, and CBC should be monitored every 1-3 months during stable long-term therapy, with clinical assessment for side effects at each visit. 1, 4
Withdrawal for gastrointestinal toxicity declines over time, but vigilance for other adverse effects must continue. 2
Combination Therapy Considerations
If disease control becomes inadequate on methotrexate monotherapy, adding a biologic DMARD or targeted synthetic DMARD is preferred over discontinuing methotrexate entirely. 5
The 2021 American College of Rheumatology guidelines emphasize maximizing methotrexate use as the "anchor" for combination therapy, with methotrexate continued as the backbone when adding biologics. 5
At 12 years, only 17% of patients were continuing methotrexate monotherapy without additional DMARDs, indicating that many patients require combination therapy over time while maintaining methotrexate. 2
Specific Scenarios Requiring Temporary Discontinuation
Methotrexate can be safely continued in the perioperative period for RA patients undergoing elective orthopedic surgery, with studies showing no increased postoperative complications and fewer RA flares when continued. 1
Methotrexate should be stopped temporarily during severe infection or when infection is not responding to standard treatment, but can be restarted when the infection has cleared. 1
Methotrexate must be stopped at least 3 months before planned pregnancy for both men and women and should not be used during pregnancy or breastfeeding. 1
Common Pitfalls to Avoid
Do not discontinue methotrexate prematurely based on the assumption that long-term use is inherently dangerous—the evidence shows sustained benefit with acceptable toxicity over decades. 1, 2
Do not stop methotrexate when adding biologics or other DMARDs, as combination therapy with methotrexate as the backbone is superior to switching away from methotrexate. 5
Do not assume that patients who have been stable on methotrexate for years no longer need regular monitoring—surveillance for hepatotoxicity, bone marrow suppression, and pulmonary toxicity must continue indefinitely. 1, 2